Process and composition for treating disorders by administering isoxsurpine and choline

ABSTRACT

Choline or a natural or synthetic compound that dissociates to form choline is administered to a patient concomitantly with a drug in order to potentiate the effect of the drug by increasing acetylcholine levels in the brain or other tissues, and/or to suppress, or block the development of, unwanted side effects of the drug, by increasing acetylcholine levels in the brain or other tissues.

The Government has rights in this invention pursuant to Grant No.MH-28783 from the National Institute of Mental Health.

REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 126,124 filedFeb. 29, 1980 which, in turn is a continuation-in-part of Ser. No.088,227, filed Oct. 7, 1979, which, in turn, is a continuation of Ser.No. 847,967, filed Nov. 2, 1977, all now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a process and composition for theadministration of choline, or natural or synthetic compounds thatdissociate to form choline, along with a drug, in order to treat humandisorders by increasing acetylcholine levels in brain and other tissues.

There are a number of diseases which affect acetylcholine-containingneurons in the brain or other tissues, and which are treated by drugsthat cause undesired side effects by diminishing acetylcholine'srelease; there also exist diseases now treated by other drugs in whichthe potency and/or efficacy of the drugs could be improved by combiningthem with choline or natural or synthetic compounds that dissociate toform choline in order thereby to enhance the release of acetylcholine.Such diseases include both those primarily involving the brain (e.g.,diseases of higher cortical functions; psychiatric illnesses; movementdisorders) and those involving the peripheral nervous system (e.g.,neuromuscular disorders). Tardive dyskinesia is a particularly commonmovement disorder associated with inadequate release of brainacetylcholine as a result of drug administration for the initial braindisease (e.g., psychosis). Tardive dyskinesia is a choreic movementdisorder characterized by involuntary twitches in the tongue, lips, jawand extremities. It typically occurs in susceptible persons afterchronic ingestion of neuroleptic drugs and may involve an imbalance inthe postulated reciprocal relation between dopaminergic and cholinergicneurons and the basal ganglions. Thus, drugs that either blockcatecholamine synthesis (e.g., alpha-methyl-p-tyrosine), deplete thebrain of monoamines (e.g., reserpine, tetrabenazine) or antagonizedopamine's actions on synaptic receptors (e.g., phenothiazines,haloperidol) often suppress tardive dyskinesia, whereas drugs thatindirectly stimulate dopamine receptors (e.g., emphetamine, levodopa)often exacerbate the abnormal movements. Drugs assumed to increase theamount of acetylcholine within brain synapses (e.g., physostigmine,deanol), also tend to suppress the chorea of tardive dyskinesia, whereasanticholinergics (e.g., scopolamine), make it worse.

We have shown that choline administered by injection or by dietarysupplementation increases blood choline levels in the rat; this, inturn, increases choline levels in cholinergic neurons within the brainand elsewhere in the body, thereby accelerating the synthesis ofacetylcholine, increasing tissue acetylcholine levels, and increasingthe amounts of acetylcholine released into brain synapses. In humanbeings, oral doses of choline or of lecithin, a naturally-occurringcompound that dissociates to choline were found to cause dose-relatedincreases in blood choline levels of sufficient magnitude (based on thestudies on rats) to enhance brain acetylcholine synthesis and release;choline levels in the cerebrospinal fluid also rose in parallel. It hasalso been reported in four human patients that the administration ofcholine decreased the choreiform movements of tardive dyskinesia; nodata were provided as to whether or not the drug given concurrently forpsychosis (halo-peridol, 3 mg per day) continued to be effective duringthe brief period of choline administration, and it was concluded thatthe apparent effectiveness of choline had to be interpreted withcaution, since ". . . all four patients with tardive dyskinesia couldhave been gradually improving during the study" since this disease ischaracterized by extreme variability of clinical course. Thus, prior toour invention, it had not been known that the concomitant administrationof choline or of a natural or synthetic compound that dissociates toform choline along with an anti-psychotic drug that causes tardivedyskinesia as a side effect could significantly reduce or prevent theonset of tardive dyskinesia, without blocking the effectiveness of thedrug in treating psychosis.

SUMMARY OF THE INVENTION

This invention is based upon the discovery that choline or aphysiologically-acceptable natural or synthetic compound thatdissociates to form choline, when administered concomitantly with adrug, can, by increasing neuronal acetylcholine levels, (1) reduce orprevent undesirable side effects of the drug associated with inadequateacetylcholine release, and/or (2) potentiate the effectiveness of thedrug. The choline and drug may be administered orally such as in tablet,capsule or liquid form or parenterally by intravenous, intramuscular orsubcutaneous injection. The process of this invention is useful evenwith patients having a prior history of the undesirable side effect orof suboptimal therapeutic response, or of therapeutic responsesrequiring a very large drug dose, but who continue taking the drug.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

In accordance with this invention, choline or a compound thatdissociates to form choline is orally administered to a patient prior toor together with a drug in order to increase blood levels of choline,and thereby to increase the level of acetylcholine in the brain. Theacetylcholine is synthesized from choline and acetyl CoA in a reactioncatalyzed by choline acethyltransterase (CAT). It has been found thatthe administration of choline or a compound that dissociates to formcholine potentiates the drug by reducing the incidence or suppressingside effects of the primary drug and/or that lower dosages of theprimary drug are needed to attain the desired effects of the drug. Whilethe results obtained will vary from patient to patient, the reduced sideeffects and increased efficacy observed are sufficiently significant asto justify the conclusion that their reduction is caused byadministration of choline or a compound that dissociates to formcholine.

There are a number of brain and peripheral diseases involvingcholinergic neurons that are presently treated with drugs that are onlysometimes effective, or that require very large doses of the drugs (withcorrespondingly greater cost and incidence of side effects); some ofthese diseases can be more effectively treated by combining the existingdrug therapy with concomitant choline or natural or synthetic compoundsthat dissociate to form choline. One example is the mania phase ofmanic-depressive psychoses, which is currently treated with lithiumsalts. These salts, as a biochemical side effect, interfere with theuptake of choline into the brain; this tends to reduce brainacetylcholine levels, which exacerbates the mania. The co-administrationof choline with the lithium salts would allow more effective treatmentof the mania, and a reduction in the lithium dose needed by mostpatients. Another example is myasthenia gravis, a peripheral diseaseinvolving the cholinergic nerves that innervate skeletal muscle. Thecurrent mode of treatment involves giving drugs like neostigmine(Prostigmin) that increase acetylcholine levels in neuromuscularsnyapses by blocking the degradation of this neurotransmitter. Werecholine or a natural or synthetic compound that dissociates to formcholine to be given concomitantly with the cholinesterase-inhibitor, theresulting increases in acetylcholine levels would both potentiate theeffect of the cholinesterase-inhibitor and allow for a reduction in itsdose.

Some of the drugs utilized in the present invention are those whichcause significant undesirable effects. Representative of such drugs areneuroleptics, such as the phenothiazines including thioridozine(MELLARIL®), fluphenazine (PROLIXIN®) trifluoperazine and chlorpromazine(THORAMINE®); the thioxanthenes including chlorprothixene (TARACTON®)and thiothixene (NAVANE®); the butyrophenones including haloperidol(HALDOL®) and indolic compounds including molindone (MOBAN®) that areused in the treatment of such diseases as schizophrenia, Huntington'sdisease and Tourette's syndrome. Other drugs that cause undesiredeffects include psychomotor stimulants such as amphetamine (DEXADRINE®),and methylphenidate (RITALIN®) that are used to treat patients withminimal brain dysfunction, hyperactivity and specific dyslexias.

The effects of some other drugs utilized in this invention arepotentiated. Representative of such drugs are: (1) isoxsuprine(VASODILAN®) and dihydroergotamines (HYDERGINE®) that are used in thetreatment of senility; (2) gluco-cortico-steroids such as triamcinotone(ARISTOCORT®) and predinsone (METICORTEN®) and anti-cholinesterase drugssuch as neostigmine (PROSTIGMIN®) and pyridostigmine (MESTINON®) thatare used to treat neuromuscular diseases, including polymyositis andmyasthenia gravis; (3) lithium (ESKALITH®) that is used to treatmanic-depressive illness and (4) tranquillizers such as phenobarbitol(LUMINAL®), and diazepam (VALIUM®) that are used to treat anxietypsychoneurosis.

The choline can be administered as choline salts, such as the chloridebitartrate or the like, or as a compound that dissociates to choline,such as an acylglycerophosphocholine, e.g., lecithin, lysolecithin,glycerophosphatidyl choline, mixtures thereof or the like. By the termacylglycerophosphocholine as used herein is meant a coumpound of theformula: ##STR1## wherein FA₁ and FA₂ can be the same or different andare fatty acid residues having from 6-26 carbon atoms, usually 16-24carbon atoms and can be saturated or unsaturated such as palmitic acid,palmitoleic acid, stearic acid, oleic acid, linoleic acid, eicosenoicacid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid,linolenic acid, mixtures thereof or the like. The fatty acid residues ofthe acylglycerophosphocholine can be varied easily by contacting theacyglycerophosphocholine, e.g., a lecithin with phospholipase A1 or A2(to cleave one fatty acid residue) or then phospholipase B (when desiredto cleave both fatty acid residues) and then contacting the cleavedcompound with the fatty acid of choice. These choline producingcompounds also can be administered to patients having lower than normalplasma choline levels, such as patients experiencing renal dialysis. Itis preferred to employ an acyglycerophosphocholine, e.g., lecithin asthe choline source since it is not degraded in the gut in contrast tocholine. The choline or compound that dissociates to choline isadministered so that a choline level of at least about 20-30nanomoles/ml and usually between about 10 and 50 n moles/ml is attainedin the patient's bloodstream. For example, when administering cholinechloride in the form of capsules or tablets, suitable dosages are fromabout 1 to 30 g/day, preferably 3-20 g/day taken in divided doses 500 to1000 mg/cap or tab. When choline chloride is administered in liquid formadmixed with a conventional liquid carrier such as a sweetened elixir orthe like, from about 1 to 10 grams/15 ml, preferably from about 2 to 5grams/15 ml can be utilized. When utilizing lecithin in a liquidcarrier, it is administered in amounts of between about 0.1 and 50grams/day. When lecithin is administered in granular form, as a tabletor in a capsule, it is employed in amounts of between about 0.1 and 100g/day, usually between about 30 and 50 g/day. Normally, lecithin is notavailable as a pure compound and is available in admixture with otherphospholipids wherein the lecithin comprises about 20-30 weight percentof the mixture.

In the process of this invention, the choline or compound thatdissociates to choline is administered prior to or concomitantly withthe drug. When administered prior to the drug, the period of timebetween choline administration and drug administration must be less thanwhen acetylcholine concentration reduction begins to occur in the brain.Generally, the period of time between administrations is less than about36 hours, preferably less than about 24 hours.

The following example illustrates the present invention and is notintended to limit the same.

EXAMPLE I

This example illustrates that choline significantly reduces tardivedyskinesia in patients taking antipsychotic drugs.

20 subjects were selected at random from a large group of inpatientswith stable chronic buccal-lingual-masticatory dyskinesia. Each patienthad received phenothiazines or haloperiodol in the past, and 13 werestill taking such drugs when the study began (Table I). Anticholinergicmedications (benz-tropin or thihexyphenidyl) were discontinued duringthe study, but the doses of all other medications, includingneuroleptics, were unchanged.

The severity of the chorea was illustrated by counting the number of eyeblinks, tongue protrusions, slow tongue movements inside the mouth, jawclosures or lip movements visible during a 30-second interval. Eachpatient sat in a quiet private room with 3 observers, one of whom waspresent during all examinations. Two observers counted the movementsindependently on two separate days before the study began and madesubsequent counts every three days thereafter. The mean counts weretabulated during the control periods, the second week of choline and thesecond week of placebo ingestion and scored the percentage change asfollows: -25 to +25 percent, no change (i.e., falling within theanticipated day-to-day variation); 25 to 50 percent, moderately changed;and >50 percent greatly changed.

Choline chloride (150 mg per kilogram per day during the first week and200 mg per kilogram per day during the second week) was mixed in a sweetcommercial beverage and dispensed in three daily divided doses. Theplacebo, sucrose octa acetate, was also dissolved in the beverage (10 mgper liter) and administered in the same manner and volume as thecholine. Both solutions tasted bitter, but the placebo did not impartthe "fishy" odor sometimes noted in patients who chronically ingestcholine.

Half the patients received choline, and the other half placebo, for twoweeks; these schedules were reversed after a 10-day interval duringwhich neither choline nor placebo was dispensed.

Blood samples for choline measurements were collected from every patientbefore the drug trial began and on three subsequent occasions: duringthe second week of therapy, on the ninth day of the drug-free intervaland during the second week of the crossover period (the final two weeksof therapy) all blood samples were collected before breakfast. Duringthe treatment periods, they were obtained one hour after the subjectsingested the beverage. Serum samples were separated, frozen and assayedfor choline content by a conventional radio-enzymatic method.

The chemical characteristics of the 20 patients with tardive dyskinesiaare set forth in Table I.

                                      TABLE I                                     __________________________________________________________________________                       Severity of                                                Case                                                                             Age   Primary   Tardive                                                                             Current  Dosage                                      No.                                                                              yr.                                                                              Sex                                                                              Diagnosis Dyskinesia                                                                          Medication                                                                             mg/day                                      __________________________________________________________________________    1  36 F  Schizophrenia                                                                           Moderate                                                                            Thiothixene                                                                            100                                         2  55 F  Schizophrenia                                                                           Moderate                                                                            Chlorpromazine                                                                         300                                                                  Trifluoperazine                                                                        40                                          3  38 F  Schizophrenia                                                                           Moderate                                                                            Haloperidol                                                                            15                                                                   Phenytoin                                                                              300                                                                  Phenobarbital                                                                          100                                         4  75 F  Senile dementia                                                                         Severe                                                                              Thioridazine                                                                           75                                          5  63 M  Schizophrenia                                                                           Severe                                                                              Phenytoin                                                                              300                                         6  85 F  Senile dementia                                                                         Severe                                                                              Diazepam 8                                                                    Phenytoin                                                                              300                                         7  79 F  Schizophrenia                                                                           Moderate                                                                            None     --                                          8  66 F  Mental retardation                                                                      Severe                                                                              Phenytoin                                                                              300                                                  with psychosis                                                       9  73 F  Schizophrenia                                                                           Severe                                                                              None     --                                          10 48 F  Schizophrenia                                                                           Severe                                                                              Haloperidol                                                                            5                                                                    Phenobarbital                                                                          120                                         11 72 F  Schizophrenia                                                                           Moderate                                                                            Chlorprothizene                                                                        150                                         12 80 F  Schizophrenia                                                                           Severe                                                                              Thioridazine                                                                           50                                                                   Diphenhydramine                                                                        100                                         13 63 F  Schizophrenia                                                                           Mild  Thioridazine                                                                           300                                         14 52 F  Schizophrenia                                                                           Mild  Chlorpromazine                                                                         100                                                                  Phenytoin                                                                              300                                                                  Phenobarbital                                                                          100                                         15 62 F  Schizophrenia                                                                           Moderate                                                                            None     --                                          16 37 M  Schizophrenia                                                                           Mild  Fluphenazine                                                                           25                                          17 76 M  Senile dementia                                                                         Severe                                                                              Diphenhydramine                                                                        50                                          18 32 M  Mental retardation                                                                      Moderate                                                                            Haloperidol                                                                            40                                                   with psychosis  Phenytoin                                                                              300                                         19 37 F  Mental retardation                                                                      Severe                                                                              Phenytoin                                                                              300                                                  with psychosis  Phenobarbital                                                                          160                                         20 66 M  Schizophrenia                                                                           Mild  Thioridazine                                                                           400                                         __________________________________________________________________________

Before treatment, plasma choline levels ranged between 8.6 and 20.5 nmolper milliliter (12.4±1.0, mean±S.E.M.). During the second week ofcholine ingestion (200 mg per kilogram per day), plasma choline levelsin blood obtained one hour after a choline dose increased in allpatients and ranged between 18.2 and 60.1 nmol per milliliter (33.5±2.5,mean±S.E.M., a 170 percent increase; P<0.001 by Student's t-test).Plasma choline levels measured during placebo administration and at theend of the 10-day "washout" period did not differ significantly fromcontrol levels.

Buccal-lingual-masticatory movements lessened in nine patients duringthe period of choline administration; five patients during the period ofcholine administration improved greatly and four improved moderately(Table II).

                  TABLE II                                                        ______________________________________                                        Clinical Effect of Choline Administration on the                              Bucal-Lingual-Masticatory Movements in 20 Patients                            with Tardive Dyskinesia                                                                        Mean No. of                                                                   Movements/                                                              No. of                                                                              30 Sec        %                                                           Pat-    Before   During Change                                   Classification                                                                             ients   Choline  Choline                                                                              Range                                    ______________________________________                                        Greatly improved                                                                           5       12.6     4.2    +74-+84                                  Moderately improved                                                                        4       21.2     11.7   +41-+55                                  Unchanged    10      13.4     13.6   +18--21                                  Worsened     1       4.5      27.5   -511                                     ______________________________________                                         * +indicates improvement and -worsening of the chorea                    

Case 1 had rapid, tremulous tongue movements, which virtually ceasedduring choline therapy. Cases 2 and 3 had slower, rolling tonguemovements within the mouth; these movements, too, were greatlysuppressed during choline treatment, but not during placeboadministration.

Tongue movements also decreased markedly, but not completely, in twopatients with more severe dyskinesia. Case 4 protruded her tongue("serpent's tongue") 20 times per 30 seconds during the initialobservation period. In the final week of choline therapy, the ratedecreased to five times per 30 seconds, although the tongue continued toroll inside her mouth. (Placebo ingestion had no effect on the rate oftongue protrusions.) Two weeks after she stopped taking choline, hertongue protrusions returned to their pretreatment rate of 20 per 30seconds. Within a week of the beginning of a second course of cholinetreatment (200 mg per kilogram per day), the rate of tongue protrusionsagain decreased to six times per 30 seconds.

Case 5 protruded his tongue 20 to 30 times per 30 seconds during initialobservations but did not protrude it at all during the second week ofcholine ingestion. It continued to move inside his mouth, but themovement frequency decreased by 49 percent.

Buccal-lingual-masticatory movements decreased moderately (25 to 50percent) in another four subjects. Cases 6 and 7 had fewer jaw movementsduring choline ingestion, but their tongue motions did not change. Thenumber of jaw movements also diminished during choline therapy in Case8, although the frequency of her eye blinks did not change. Tongue andlip movements decreased during choline ingestion in Case 9, but jawmovements were unaffected.

The frequency of tongue movements increased markedly in Case 20 (fromfour to 27 times per 30 seconds) during the period of choline ingestion,but returned to control counts when the choline was discontinued.Neither choline nor placebo altered buccal-lingual-masticatory movementsin the remaining 10 patients.

Another patient with severe akathisia was included in the study; she didnot exhibit facial chorea, however, and is not listed in the tables. Shewas unable to sit still and moved her feet 30 times every 30 seconds.These movements were not altered during placebo ingestion but nearlyceased during choline administration.

No serious side effects were encountered in any subject during thecourse of the study. Cases 2 and 3 were more withdrawn than usual andpossibly depressed during choline treatment. Three patients (Cases 4, 7and 15) experienced symptoms of mild cholinergic toxicity, includinglacrimation, blurred vision, anorexia and diarrhea, while taking 200 mgof choline per kilogram per day. All the effects were dose related andsubsided when the dosage was reduced.

The patients who participated in the study all exhibited permanentbuccal-lingual-masticatory characteristic of tardive dyskinesia and allhad taken neuroleptics in the past (although these drugs had beendiscontinued in seven patients before the study began). Most subjectswere elderly women who had taken neuroleptics for many years; the drugsand doses listed in Table I are minimal estimates. Since the onset oftardive dyskinesia was documented only in Case 13, it is possible thatsome patients in the series had senile chorea, or the mannerisms ofmentally retarded or psychotic patients, and not true drug-inducedtardive dyskinesia. The variety of their responses to choline (ninebetter, one worse and 10 unchanged) suggests that the patient sample wasindeed heterogeneous at least in the involvement of cholinergicmechanisms. This confusion about causes will remain a problem until anaccurate diagnostic test for tardive dyskinesia is found.

Most attempts to treat tardive dyskinesia are based on the theory thatneuroleptic drugs, by blocking intrasynaptic dopamine receptors, cause areflex overactivity of dopaminergic neurons, which may be due toincreased dopamine turnover or to "denervation" supersensitivity. Eitheraction would excessively suppress striatal cholinergic neurons (whichreceive inhibitory impulses from the dopaminergic nigrostriatal pathway)at times of day when the blockade of dopamine receptors was incomplete.Although no therapy is completely satisfactory, numerous efforts totreat stable tardive dyskinesia have employed drugs thought to decreasethe amount of dopamine released into central synapses. Other therapeuticstrategies designed to increase cholinergic tome at the next synapsedistal to that employing dopamine have had only limited success.

Buccal-lingual-masticatory movements decreased in nine patients duringthe period of choline consumption, but were unaffected by the placebo.The occurrence of cholinergic side effects in three of the subjectsprovides additional indirect evidence that exogenous choline enhancesneuronal acetylcholine synthesis and release in human beings andprobably accounts for the suppression of chorea in the nine patients whoimproved during choline therapy. The buccal-lingual-masticatorymovements of these patients were not sufficiently different from thosedisplayed by the group as a whole to permit identification of particularmovements that might be especially responsive to choline treatment.

The mean blood choline levels, both before and during treatment, in thepatients who responded to choline did not differ significantly from themean of the group as a whole--in nine responders, 13.1±1.4 nmol permilliliter before and 31.5±2.5 during treatment, and in the entiregroup, 12.4±1.0 nmol per milliliter before and 33.5±2.5 duringtreatment--nor did their age (63.3 years vs. 59.8 years) sex(predominantly women), primary diagnosis (predominantly schizophrenia),or concurrent neuroleptic medication (Table I).

Oral doses of lecithin, the major source of dietary choline, may be analternate way to treat patients with tardive dyskinesia. We observe thatlecithin administration, like that of free choline, elevates bloodcholine levels in human subjects.

We claim:
 1. The process of reducing or eliminating undesirable sideeffects of a drug administered to a human which side effects result frominadequate release of brain acetylcholine, said drug being selected fromthe group consisting of isoxsuprine and dihydroergotamine, whichcomprises administering concomitantly with the drug an amount of acompound effective to release adequate amounts of brain acetylcholineand to raise the blood concentration of choline in the human to betweenabout 10 and about 50 n moles/ml selected from the group consisting ofcholine, a salt of choline, lysolecithin and acyglycerophosphocholine,glycerophosphatidyl choline and mixtures thereof.
 2. The process ofclaim 1 wherein the drug and the compound are administered together as acapsule or tablet.
 3. The process of claim 1 wherein the drug and thecompound are administered together in a liquid.
 4. The process of claim1 wherein the compound is an acyglycerophosphocholine.
 5. The process ofclaim 4 wherein the acyglycerophosphocholine is lecithin.
 6. The processof claim 1 wherein the compound is choline chloride.
 7. A composition ofmatter comprising (a) a drug which, when administered to a human causesside effects associated with inadequate release of brain acetylcholine,said drug being selected from the group consisting of isoxsuprine and adihydroergotamine and (b) an amount of a compound effective to releaseadequate amounts of brain acetylcholine and to increase the cholinelevel of a patient to between about 10 and 50 n moles/ml selected fromthe group consisting of choline, a salt of choline, lysolecithin, anacyglycero phosphocholine having the formula: ##STR2## wherein FA₁ andFA₂ can be the same or different and are fatty acid residues having from6-26 carbon atoms, glycerophosphatidyl choline and mixtures thereof. 8.The composition of claim 7 wherein the compound is anacyglycerophosphocoline.
 9. The composition of claim 8 wherein theacyglycerophosphocholine is lecithin.
 10. The composition of claims 7, 8or 9 wherein the compound is choline chloride.
 11. The composition ofany one of claims 7, 8, 9 or 10 wherein the drug is isoxsurpine.
 12. Thecomposition of any one of claims 7, 8, 9 or 10 wherein the drug isdihydroergotamine.